Postpartum depression is a mood disorder that occurs in some women following the birth of a child. Common symptoms include feelings of extreme sadness, loneliness, anxiety, and exhaustion, and mirror those of Major Depressive Disorder with the additional criteria that the onset of symptoms begins within 4 weeks of childbirth. In some cases sufferers can develop psychosis. Rapidly declining postpartum progesterone and allopregnanolone levels are thought to contribute to the development of postpartum depression. The CDC estimates between 10-15% of mothers experience postpartum depression within a year of giving birth, with approximately 7% of women experiencing postpartum depression within three months of delivery. The rates are likely higher in developing countries. Few women, likely less than 15% seek medical treatment for the symptoms of postpartum depression. When treated, the most commonly used medications are Selective Serotonin Reuptake Inhibitors (SSRI's) and Serotonin-norepinephrine Reuptake Inhibitors (SNRI's), medications than require several weeks to take effect. Allopregnanolone has previously been administered as an intravenous infusion to women suffering from postpartum depression, and found to be strongly efficacious in placebo-controlled studies. All women in the study were suffering from postpartum depression and exhibited a Hamilton Depression Rating Scale (HAM-D) baseline score of greater than 25. At the end of a sixty hour infusion patients has a mean HAM-D score 12 points lower than placebo-treated subjects. The 12 point difference in HAM-D score from placebo is larger than the typical 3 to 5 point difference observed in clinical studies for other antidepressants. Allopregnanolone's effects were also found to be long lasting, persisting 30 days after infusion, although more work needs to be done to understand the duration of the antidepressant effect.
Premenstrual dysphoric disorder (PMDD) is a severe form of premenstrual disorder, in which a women experiences depressed mood, mood swings, irritability, anxiety, and changes in sleep and appetite as well as disturbance in functioning at home and/or work prior to menstruation. The Diagnostic and Statistical Manual (DSM-V) provides criteria for diagnosing PMDD. Symptoms associated with PMDD are confirmed by prospective self-ratings that are tracked for at least two complete menstrual cycles. For diagnosis with PMDD a patient must experience at least 5 of the listed criteria for two consecutive menstrual cycles. Approximately 3-8% of women of reproductive age experience premenstrual symptoms severe enough to meet the DMS-V criteria for PMDD. Standard of care treatment for PMDD includes SSRIs, which are considered effective, but require several weeks to provide relief. The symptoms of PMDD begin sometime after ovulation, but typically around five days before menses and peak the day before menses or the first day of menses. Symptoms of PMDD respond to treatment with a serotonin reuptake inhibitor (SRI) even when medication is administered for half of the menstrual cycle (2-4) or at symptom-onset. (5, 6) This is atypical since SRIs require weeks to show therapeutic activity for a major depressive episode, panic disorder or generalized anxiety disorder. Given the short onset of therapeutic action of SRIs for PMDD, some hypothesize that SRIs work via a unique mechanism that enhances the production of neuroactive steroids rather reuptake blockade of serotonin. Declining levels of allopregnanolone in the late luteal phase are thought to contribute to PMDD. SSRIs are known to increase allopregnanolone levels and SSRI administration during the late luteal phase is known to alleviate PMDD symptoms.
Postmenopausal depression is a form of major depressive disorder (MDD) with considerable unmet medical need; it is often treatment resistant. Approximately 70% of patients do not respond to standard treatment. Only 30% of patients with postmenopausal depression achieved remission after 8-12 weeks of SSRI therapy. Allopregnanolone levels are inversely correlated with the severity of anxiety and depression symptoms in women across the weight spectrum. Traditional antidepressants may improve depression symptoms by increasing allopregnanolone levels. Allopregnanolone levels are known to increase as major depressive disorder symptoms improve.
Allopregnanolone has been implicated as a treatment for each of the female depressive disorders, postpartum depression, premenstrual dysphoric disorder, and treatment resistant postmenopausal depression. However, allopregnanolone has drug properties that reduce its desirability as a treatment and limit its utility. Allopregnanolone has a short half-life and it cannot be administered orally. While infusion treatment is appropriate for severely depressed patients, many patients would benefit from a pharmaceutical treatment that could initially be administered in an injectable form but that could also be orally administered for longer term therapy. Thus additional treatments may effect improvement through a similar mechanism are desired.
Delirium Tremens (DT) is a severe form of alcohol withdrawal. Onset often occurs 48 to 96 hours after the last drink and it marked by a rapid onset of acute confusion and profound disorientations. DT sufferers may experience tactile, auditory, and visual hallucinations and can experience seizures. ICU hospitalization is recommended. The first line of treatment high dose benzodiazepine; propofol and general anesthesia are administered in refractory cases. Escalating high doses of phenobarbital have also been used clinically. DT can be fatal and has a mortality rate of about 0.5 to 1%. In the US there are approximately 35,000 cases of DT annually with an aggregate cost of treatment of approximately $375 million. There are currently no FDA approved drugs for treating DT and there are no reports of any being developed. Improved treatments for DT that can result in faster recovery, shorten the duration of inpatient hospitalization, and reduce the time of ICU treatment.